Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patient's ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. Serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patient's nonketotic sera, normal sera, or Trasylol. Glutathione-insulin-transhydrogenase (GIT) activity was 66% of normal. The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP). The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.
Diabetes 1979 Jul
PMID:Insulin resistance caused by massive degradation of subcutaneous insulin. 10 40

The disappearance rate of intravenously injected insulin was investigated in the serum of 30 women during the third trimester of pregnancy and 6 to 8 weeks post partum, in order to determine whether pregnancy has an influence on insulin kinetics in human subjects. Both women with unimpaired glucose tolerance and those with latent diabetes were included in this study. The disappearance rate of exogenous serum insulin in pregnancy was characterized by a two-compartment model. Multivariate analyses of variance were used to determine whether the estimated parameters of this model during pregnancy differ from those obtained after the puerperium and whether the insulin kinetics are altered when carbohydrate metabolism is disturbed. The kinetics of insulin during pregnancy did not differ from those after pregnancy. Thus, hyperinsulinemia observed in pregnancy cannot be explained by a change in the insulin kinetics. It appears improbable that the insulin-degrading enzyme activities of the placenta participate in degradation of insulin circulating in the maternal blood. A connection between the decline of glucose tolerance during pregnancy and the kinetics of exogenous insulin could not be found.
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PMID:Influence of pregnancy on the kinetics of insulin. 114 34

This study compares some properties of the immunoreactive insulin-like material extracted from the urine of children with overt diabetes with that from normal children. Insulin-like species were fractionated by gel filtration and by isoelectric focusing and were tested for sensitivity to an insulin-specific degradative enzyme. Insulin concentration was measured by radioimmunoassay. The major insulin-like component from the urine of ten normal children and fifteen untreated juvenile diabetics and from the urine of four and the serum of one latent diabetics behaved (on gel filtration) as normal insulin, was sensitive to insulinase, and (in all cases studied) had an identical isoelectric point (resolution 0.1 pH units). A proportion of the immunoreactivity extracted from urine (0-4 per cent from normal children, 5-30 per cent from twelve of the thirteen nonobese untreated diabetic children) eluted from the gel filtration column before insulin. This material from diabetic urine was of two size classes, "proinsulin-like" and "mid-insulin," both resistant to degradation by insulinase. Insulinase-resistant immunoreactivity from one patient was analyzed by isoelectric focusing. Urine samples from two obese children with overt diabetes and four children with latent diabetes contained normal proportions (less than 4 per cent) of immunoreactive species larger than insulin. The possible nature and significance of the present insulinase-resistant species are briefly considered.
Diabetes 1975 Jul
PMID:Insulin-like insulinase-resistant material, distinguishable from normal insulin, in juvenile diabetes. 117 3

The degradation of native and 125I-labeled human insulin (HI) was examined in the cytosolic fraction of human, monkey, and rat liver. The purpose of these studies was to provide a species comparison of the interaction of insulin-degrading enzyme (IDE) and protein disulfide isomerase (PDI) in the degradation of HI. Western-blot analysis with monoclonal antibodies indicated the presence of both IDE and PDI in the cytosolic fraction of human and monkey liver. In contrast, rat liver cytosol contained, detectable levels of IDE only. A species comparison of metabolic profiles was performed by fractionating peptide products with reversed-phase high-performance liquid chromatography. After a 60-min incubation, human liver cytosol degraded unlabeled HI into three major products. Two of these peptides coeluted with the products of the incubation of HI with purified rat liver PDI. The three peptides were isolated and determined by NH2-terminal sequence analysis to be intact A chain, B chain, and des(Phe1)-B chain. Human liver cytosol also formed 125I-A chain and 125I-B chain as major products when specifically labeled 125I-HI isomers were used as substrate. Significant proteolytic degradation was observed only when reactions with human liver cytosol were supplemented with Mn2+. In contrast, monkey and rat liver cytosol proteolytically degraded 125I-HI isomers to small peptide fragments. The rat and monkey metabolic profiles were similar to each other and to that observed with Mn(2+)-supplemented human liver cytosol. Proteolysis in monkey and rat was sensitive to inhibition by EDTA.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Apr
PMID:Mechanisms involved in degradation of human insulin by cytosolic fractions of human, monkey, and rat liver. 160 78

The nature of insulin degradation within endosomes was studied in vitro. Radiolabeled insulin was perfused into rat liver via the portal vein, and insulin-containing endosomes were prepared by differential centrifugation. The endosomes were incubated in various buffers, and hormone degradation was monitored by Sephadex G-50 chromatography and high-performance liquid chromatography (HPLC). Endosomes incubated in simple imidazole or HEPES (pH 7.4) buffers rapidly degraded insulin to intermediate- and then to low-molecular-weight products that were lost from the vesicles. HPLC analysis of insulin-sized material showed the products to be the same as those produced by intact cells. The endosomes did not acidify in these buffers (as assessed by the acridine orange method), and ATP had no effects. When the endosomes were incubated in a chloride-containing buffer, degradation was greatly inhibited, and acidification did not occur. Both insulin degradation and acidification were activated when Mg-ATP was added to this buffer system. HPLC analysis of the products generated in this system revealed not only typical cellular products but additional less hydrophobic products. Western-blot analysis of endosomal protein with anti-insulin-degrading enzyme antibody showed this enzyme to be present. In conclusion, isolated endosomes rapidly and completely degrade insulin through products that are typical of cellular degradation without requiring acidification. Chloride-containing buffers inhibit endosomal degradation, which is reversed by Mg-ATP, but this system does not mimic cellular degradation. At least one of the enzymes responsible for insulin degradation is insulin-degrading enzyme.
Diabetes 1991 Apr
PMID:Degradation of intraendosomal insulin by insulin-degrading enzyme without acidification. 201 43

Five monoclonal antibodies specific for glutathione-insulin transhydrogenase were characterized. None of the monoclonal antibodies cross-reacted with another insulin-degrading enzyme, neutral thiopeptidase. The isotype of four antibodies was IgG1 and of the fifth IgG2b. Affinity studies, competitive binding studies and immunoblot analysis of CNBr and trypsin cleavage products of glutathione-insulin transhydrogenase demonstrated that the four IgG1 antibodies were directed to an epitope of the enzyme which was distinct from the epitope recognized by the IgG2b antibody. Inhibition studies indicated that each monoclonal antibody, when added singly to glutathione-insulin transhydrogenase, was unable to inhibit the insulin-degrading activity of the enzyme. However, when monoclonal antibodies directed against separate epitopes of glutathione-insulin transhydrogenase were presented together (i.e., the IgG2b with any one of the four IgG1 antibodies), a loss in enzymatic activity was noted. Immunoblot analysis of rat organ extracts with the IgG1 antibodies demonstrated one immunoreactive protein band of Mr 56,000 in all tissues examined (liver, fat, pancreas and kidney) except the spleen, which demonstrated two immunoreactive protein bands of Mr 56,000 and 51,000. The same immunoblots, when probed with the IgG2b antibody, demonstrated the same immunoreactive protein banding pattern as above plus an additional immunoreactive protein band of Mr 67,000 in all tissues. Studies with spleen extracts from steptozotocin-induced diabetic rats demonstrated that there was a loss of the 51,000 immunoreactive band in diabetes. This 51,000 protein was restored upon insulin treatment of the diabetic rats and nullified upon concomitant administration of cycloheximide or actinomycin D with insulin. Immunoblots of human liver, adipose and skeletal muscle extracts indicated that each monoclonal antibody cross-reacted with the human form of the enzyme which had a molecular weight of Mr 63,000; a second minor immunoreactive band of 67,000 was detected with the IgG2b antibody. The physiological significance of additional molecular forms of the enzyme (i.e., 67,000 and 51,000) remains to be determined.
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PMID:Characterization and application of monoclonal antibodies directed to separate epitopes of glutathione-insulin transhydrogenase. 243 25

An insulin-degrading enzyme has been purified from human erythrocytes. This enzyme degraded 125I-labeled insulin-like growth factor I (IGF-I) more slowly than 125I-IGF-II and degraded IGF-II more slowly than 125I-insulin. The time course of 125I-insulin degradation suggested the presence of intermediates, each of which was itself shown to be a substrate for the enzyme. One of these intermediates appeared to be made up entirely of B-chain residues and had HisB10 as its NH2-terminal. The final major radiolabeled degradation product of A14-[125I]monoiodoinsulin was a peptide with TyrA14 at the A-chain NH2 terminal. This peptide could be reduced with dithiothreitol, suggesting that it contained amino acid residues from both A- and B-chains. It was partially precipitated by trichloroacetic acid and anti-insulin antibody but bound poorly to IM-9 lymphocytes. The final major degradation product of B26-[125I]monoiodoinsulin was a peptide whose NH2-terminal was TyrB26 and could not be reduced by dithiothreitol. It was partially precipitated by anti-insulin antibody but was precipitated poorly, if at all, by trichloroacetic acid and bound poorly to IM-9 lymphocytes. The results show that this enzyme degraded insulin by sequential cleavage of peptide bonds on both A- and B-chains. We identified LeuA13-TyrA14, SerB9-HisB10, and PheB25-TyrB26 as three of the bonds that are cleaved.
Diabetes 1989 Feb
PMID:Degradation of insulin and insulin-like growth factors by enzyme purified from human erythrocytes. Comparison of degradation products observed with A14- and B26-[125I]monoiodoinsulin. 264 37

RIN-m cells, cultured from a rat insulinoma, not only bind and secrete but also degrade insulin (Diabetes 1982; 31:521-31). The insulin-degrading activity resides in the cytosol and is similar to the insulin-specific proteases previously described in muscle and other tissues. It has an apparent Km of 0.15 microM for porcine insulin in crude cell-free extracts, a competitive inhibition constant for proinsulin that is close to the Km, and a lower but measurable affinity for glucagon. The enzyme is inactive at pHs below 6.0, indicating that it is not lysosomal, is completely inhibited by N-ethylmaleimide, and exhibits apparent competitive inhibition constants (microM) for the following peptides: desoctapeptide insulin, 0.043; guinea pig insulin, 0.048; proinsulin, 0.64; insulin B-chain, 1.17; glucagon, 7.0; and cyclic somatostatin, 8.6. Highly active insulin-degrading activity was found using cell suspensions of 22 cloned and 8 subcloned cell lines derived from RIN-m as well as 11 other continuous cell lines derived from a variety of nonislet tissues of rat, mouse, and human origin. Homogenates of the original rat islet tumor and cytosol of normal rat islets also contained insulin-degrading activity. Although insulin protease is present in a variety of tissues, it may have an additional regulatory function in cells that are actively synthesizing, storing, and secreting insulin.
Diabetes 1985 Feb
PMID:Cytosolic insulin-degrading activity in islet-derived tumor cell lines and in normal rat islets. 298 50

The effect of age and of prolonged caloric restriction on glucose tolerance and insulin responsiveness has been studied in male Fischer 344 rats. Beginning at 1 month of age dietary intake of an experimental group (R) was limited to 60% of that of the control group (AL) which was allowed to eat ad libitum. Studies were carried out at intervals up to 24 months of age. In AL rats the oral glucose tolerance curve showed progressively higher peak levels of plasma glucose with age, and a decrease in the plasma insulin concentration at the time of the glucose peak. The R group did not show the increase in peak value with age and the corresponding insulin concentration was lower than that of the AL group. These results are compatible with a delay in the first phase of insulin secretion in aging AL rats. Insulin-stimulated glucose disposal was assessed by the method of Reaven et al. [Diabetes, 32 (1983) 175], at ages 4, 12, 18 and 24 months; using infusions of 2 mU of insulin and 1 mg of glucose/min per kg, the steady-state plasma glucose level (SSPG) was slightly lower in R than in AL rats, while the steady-state plasma insulin level was reduced by 40-60%. In rats aged 18-24 months the hepatic glucose output, measured with [3-3H]glucose, was the same for AL and R rats in the basal state and was reduced to the same extent by insulin. In the presence of epinephrine and propranolol, infusion of glucose and insulin at various rates demonstrated that the plasma glucose clearance rate increased linearly with increasing SSPI, and at comparable SSPI levels was lower in R than in AL rats. The ability of insulin to stimulate glycogenesis from glucose was measured in primary hepatocyte cultures. Insulin increased glycogenesis 3-fold in cells from AL rats and 4-6-fold in cells from R rats. There was no effect of age. The increased insulin responsiveness of R rats was not due to an increase in insulin binding or to a decrease in insulin degradation (measured with intact cells or as cytosolic insulinase activity).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of diet restriction on glucose metabolism and insulin responsiveness in aging rats. 306 1

An original method was used for a study of blood insulinase activity in patients with type I (insulin-dependent) diabetes mellitus which was decreased as compared to that in healthy persons and in persons with disturbed glucose tolerance. A GTT caused no significant variations of this index. Relations between lowered blood capability to degenerate insulin in diabetes mellitus and a rise of antiinsulinase activity of the plasma with preserved normal insulinase activity of erythrocytic hemolysate were established.
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PMID:[Blood insulinase activity in patients with diabetes mellitus]. 332 77


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